Cerebral venous thrombosis in

Argentina: clinical presentation,predisposing factors, outcomes and literature review

Matías Alet, MD,*,

† Celina Ciardi, MD,‡ Alberto Alem�an, MD,§Lucrecia Bandeo, MD,{ Pablo Bonardo, MD,{ Clarisa Cea, MD,# Juan Cirio, MD,‡

Jer�onimo Cossio, MD,| María Cuculic, MD,** María Martha Esnaola, MD,††

Fernando García-P�erez, M,‡‡ Federico Giner, MD,§§Maia G�omez-Schneider, MD,{{ Cristian Isaac, MD,## Sandra Lepera, MD,†

Carlos Martínez, MD,|| Rom�an Martínez-Lorenzín, MD,***Mariana Montes, MD,††† Gabriela Orzuza, MD,‡‡‡ Gabriel Persi, MD,§§§

Guillermo Povedano, MD,{{{ Virginia Pujol-Lereis, MD,*Julieta Quiroga-Narv�aez, MD,### Marina Romano, MD,|||

Rodrigo Sabio, MD,**** Juan Viglione, MD,††††María Cristina Zurr�u, MD,# andGustavo Saposnik, MD, MPH, FRCPC‡‡‡‡, On behalf of the Argentinian Stroke

and Cerebrovascular Diseases Study Group - Argentine Neurological Society

From the *Centro IntegRamos Mejía. Ciudad AuInstituto M�edico de Alta CBuenos Aires. Ciudad Aurando. Chaco, Argentina;pital Lagomaggiore. MenArgentina; ##Hospital Dr.Santa Fe, Argentina; †††Hla Trinidad Mitre. CiudadAires, Argentina; ###HospSAMIC de Alta Complejitina; and ‡‡‡‡Stroke OutcCanada.Received June 8, 2020; rCorresponding author:

tina E-mail: malet@fleni.o1052-3057/$ - see front© 2020 Elsevier Inc. Allhttps://doi.org/10.101

Journal of Stroke and Cer

Background: Cerebral venous thrombosis (CVT) is a rare medical condition that pri-marily affects young adults. The clinical spectrum is broad and its recognitionremains a challenge for clinicians. Limited information is available on CVT inArgentina. Our goal was to report the results of the first National registry on CVTin Argentina and to compare clinical presentation, predisposing factors and out-comes with other international registries. Material and method: The ArgentinianNational Registry on CVT (ANR-CVT) is a multicenter retrospective cohort studycomprising patients aged 18 and older with a diagnosis of CVT from January 2015to January 2019. We evaluated demographics, predisposing factors, clinical presen-tation, and radiological characteristics (e.g. number of involved sinuses, venousinfarction or hemorrhage on CT and MRI scans at admission), therapeutic interven-tions and functional outcomes at discharge and at 90 days. Our results were com-pared to a literature review of CVT registries. Results: Overall, one hundred and

ral de Neurología Vascular, FLENI. Ciudad Aut�onoma de Buenos Aires, Argentina; †Hospital General de Agudos J. M.t�onoma Buenos Aires, Argentina; ‡Clínica La Sagrada Familia. Ciudad Aut�onoma de Buenos Aires, Argentina; §IMAC -omplejidad. Salta, Argentina; {Hospital Brit�anico. Ciudad Aut�onoma de Buenos Aires, Argentina; #Hospital Italiano det�onoma de Buenos Aires, Argentina; |Hospital �Angel Cruz Padilla. Tucum�an, Argentina; **Hospital Julio Cecilio Per-††Hospital C�esar Milstein. Ciudad Aut�onoma de Buenos Aires, Argentina; ‡‡Neuromadryn. Chubut, Argentina; §§Hos-doza, Argentina; {{Instituto de Neurología y Neurocirugía. Sanatorio de los Arcos. Ciudad Aut�onoma de Buenos Aires,Arturo O~nativia. Buenos Aires, Argentina; ||Hospital Cullen. Santa Fe, Argentina; ***Hospital Provincial del Centenario.IGA Gral. San Martín de La Plata. Buenos Aires, Argentina; ‡‡‡Hospital San Bernardo. Salta, Argentina; §§§Sanatorio deAut�onoma de Buenos Aires, Argentina; {{{Complejo M�edico Policial Churruca-Visca. Ciudad Aut�onoma de Buenos

ital Dr. Guillermo Rawson. San Juan, Argentina; |||CEMIC. Ciudad Aut�onoma de Buenos Aires, Argentina; ****Hospitaldad Gobernador Cepernic - Presidente Kirchner. Santa Cruz, Argentina; ††††Clínica Regional del Sud. C�ordoba, Argen-omes and Decision Neuroscience Research Unit, Department of Medicine, St. Michael's Hospital, University of Toronto,

evision received July 5, 2020; accepted July 8, 2020.Alet Matías Javier, Centro Integral de Neurología Vascular, FLENI. Monta~neses 2325, C1428 AQK, Buenos Aires, Argen-rg.ar.matterrights reserved.6/j.jstrokecerebrovasdis.2020.105145

ebrovascular Diseases, Vol. 29, No. 00 (), 2020: 105145 1

2 M. ALET ET AL.

sixty-two patients met the inclusion criteria. The mean age was 42 (§17) years; 72%were women. Seventy percent of patients were younger than 50 years. The mostcommon presenting symptom was headache (82%). The transverse sinus was themost common site of thrombosis (70%) followed by the sigmoid sinus (46%). Themain predisposing factor in women was contraceptive use (44%), 3% of the eventsoccurred during pregnancy and 9% during the puerperium. Participants 50 yearsand older had a higher frequency on malignancy related (7.5% vs. 30%, p = 0.0001)and infections (2% vs. 11%, p = 0.001). The modified Rankin Scale (mRS) �2 at dis-charge was 81% and the rate of mortality at discharge was 4%. At 90 days, themRS�2 was 93%. When the ANR-CVT was compared with larger registries fromEurope and Asia, the prevalence of cancer among patients with CVT was two tofive-fold higher (15% vs. 7% and 3%, respectively; p = 0.002 and p < 0.001). Anticoa-gulation rates at discharge were also higher (94%) compared to registries from Asia(ASCVT � 68%) or Turkey (VENOST � 67%). Conclusion: Participants in the firstANR-CVT had a low mortality and disability at 90 days. Clinical and radiologicalcharacteristics were similar to CVT from other international registries with a higherprevalence of cancer. There was a high variability in treatment adherence to guide-lines as reflected by anticoagulation rates (range 54.5%-100%) at discharge.Keywords: Argentine—cerebral veins—cerebral venous sinus thrombosis—cerebrovascular disease—outcome—registry—stroke© 2020 Elsevier Inc. All rights reserved.

1. Introduction

Cerebral venous thrombosis (CVT) is an uncommonmedical condition that primarily affects youngindividuals. Previous studies suggest an annual incidencerate of 1-12/1,000,000 cases, representing 0.5% to 3% ofall stroke.1-4 CVT is more common in childbearingwomen, usually associated with a transient prothromboticstate (e.g. pregnancy, puerperium, exposure to oralcontraceptives).5

Most common clinical presentation among patientswith CVT include headaches, seizures, impaired con-sciousness and focal neurological signs. A high level ofsuspicion is required to make the diagnosis given thecommonalities to the clinical presentation in other neu-rological conditions (e.g. stroke, meningitis, encepha-lopathies, etc.). Approximately 5% of individuals havea more insidious course not having most common neu-rological manifestations, making the diagnosis chal-lenging. 1,2

To date, the largest multicenter CVT studies arefrom Turkey, Asia, Europe and the ISCVT(International). Limited information is available of CVTin Argentina and South America. Our intention was toevaluate most common factors and features of CVT inour population given differences in ethnic backgroundsand the prevalence of risk factors (for CVT) compared toother registries.We performed the Argentinian National Registry on

CVT (ANR-CVT), a multicenter cohort study, aiming toevaluate demographics, predisposing factors, clinical pre-sentation, radiological characteristics, therapeutic inter-ventions and modified Rankin Scale (mRS) at dischargeand at 90 days in CVT patients. Our results were com-pared to a literature review of CVT registries.

2. Methods

We are first reporting the results of the ArgentinianNational registry on CVT (ANR-CVT), a multicenter ret-rospective cohort study. Patients over 18 years old withconfirmation of cerebral venous thrombosis in either com-puted tomography (CT) with venography (CTV), mag-netic resonance (MR) with venography (MRV) or cerebraldigital subtraction angiography (DSA) were included inthis study. The reporting period comprised eligible partic-ipants from January 1st, 2015 to January 31st, 2019. Theinformation was collected by a standardized data collec-tion form from 23 participating stroke centers fromArgentina. CVT cases were identified by multiplesearches in hospital registries and neurology divisionsdatabases. We included all patients with a diagnosis ofCVT irrespective of the admission setting from all partici-pating institutions. In other words, patients with CVTadmitted to the stroke unit, neurology ward, internalmedicine ward, intensive care unit (ICU), or obstetricsand gynecology (OBG) wards were included in our study.Taking into account extrapolated data from a survey car-ried out by the Stroke Study Group - Argentine Neurolog-ical Society in 2017 (where the data showed that 72centers in Argentina had the capacity to manage acutestroke), we could estimate that we have obtained informa-tion from one-third of the centers in the country withstroke experience.As an inclusion criteria, the patient must be over 18 years-

old at the time of the clinical event. Those with incompletedata or incomplete diagnosis were excluded. Demographicdata, predisposing factors, clinical presentation, diagnosticimaging, affected cerebral venous sinuses, treatment andfunctional outcome at discharge and at 90 days measuredby modified Rankin Scale were analyzed. The mRS was

CEREBRAL VENOUS THROMBOSIS IN ARGENTINA 3

evaluated by a vascular neurology physician during an out-patient visit 90 days after admission or, if that was not possi-ble (i.e.: long distance from the institution), patients werecontacted by telephone.A comparative analysis of the data obtained by sex and

age (� 50 vs > 50 years) was performed. The cut-off pointto define young patients was considered � 50 years.Among predisposing factors, those with a known rela-

tionship to CVT were evaluated (exposure to oral contracep-tives, pregnancy, puerperium, obesity, infections, activemalignancy and thrombophilia, among others). The associa-tion with: antiphospholipid antibodies, factor V Leiden,hyperhomocysteinemia, methylenetetrahydrofolate reduc-tase gene (MTHRF) mutation, PAI 4G/5G mutation, pro-thrombin 20210 gene mutation, altered protein S andprotein C and resistance to activated protein C wereobtained when available.We defined a priori group age (� 50 vs > 50 years) and

sex group comparisons as these were common factorsreported in previous studies. Similarly, the prevalence ofthrombophilia as an association with CVT was alsodefined a priori.The study was approved by the Ethics Committee of

each center. The data obtained by each center coordinatorwas included in a standardize case-review form.

3. Literature review

3.1. Data sources

We conducted a literature search of MEDLINE, Scielo andLilacs, from January 2000 to December 2019, using a combi-nation of MeSH terms as major subjects, including: “cerebralsinus”, “cerebral venous”, “cerebral vein”, “dural sinus”AND “Thrombosis”, ‘Sinus AND Thrombosis” and “Intra-cranial AND thrombosis”, “CVT”, “registry” and “study”(or their equivalents in Spanish to include Latin Americansdatabases). Duplicate results were excluded.

3.2. Study selection

Candidate articles reporting cerebral venous thrombo-sis were included if they met the following inclusion crite-ria: First, at least more than ten patients reported. Second,basic information about demographics, predisposing fac-tor, diagnosis methods and treatment should be easilyavailable. Third, patients should be older than 18 years.Fourth, at least one outcome measure (death in hospitali-zation, disability al discharge, etc.) should be reported.Fifth, the study was written in English or Spanish.We analyzed the original data as reported by the

authors (in text and/or tables). When data was not avail-able, we tried to complete it from others sources (e.g.,additional files). We excluded the study if raw data wasnot available. We excluded isolated case reports. We alsoexcluded from our sample other types of publications (e.g. review articles, letters to Editors).

3.3. Data extraction

Two reviewers (MJA, CC) assessed the abstracts todetermine eligibility. Information was extracted in a datacollection form, including: country of origin, year of publi-cation, type of registry (retrospective, prospective), demo-graphics (age, sex), symptoms, CVT predisposing factors(e.g., prothrombotic state, infections, malignancy, etc.),cerebral venous sinus involved, treatment (e.g., anticoa-gulation, decompressive surgery, etc.) and outcomes (e.g.,death, disability at discharge, CVT recurrence, etc.).

3.4. Statistical analysis

Continuous data were summarized as mean (§ stan-dard deviation) or median (minimum - maximum) con-sidering their distribution. Categorical data werepresented as frequency and percentage. An independentt-test was used to compare groups for continuousvariables. Categorical data were analyzed using Pearson'schi-square or statistical likelihood ratio test. The collecteddata was analyzed with SPSS v.22.

4. Results

One hundred and sixty-two patients met the inclusioncriteria.Seventy-two percent of the patients were women

(n=117) (female/male ratio 2.6). Women with CVT wereyounger than men [mean age: 39.5 (§17) vs 47.5 (§18);p < 0.01]. Overall, 114 patients (70%) were under 50 yearsof age. Demographic characteristics, clinical presentation,diagnostic methods, number of affected cerebral venoussinus and associated brain lesions are shown in Table 1.Most patients were assessed in tertiary stroke care centersfrom largest cities in Argentina (e.g. City of Buenos Aires,La Plata, C�ordoba, Rosario and Tucum�an), comprising83% of all CVT reported during the study period.The median time since symptoms onset to the initial med-

ical assessment was 4 days (range: 0-74 days). Headachewas the most frequent presenting symptom in both womenand men (85% vs. 75%; p = 0.14), and 44 patients (27%) pre-sented with isolated headache. No significant differenceswere found in the clinical presentation by sex or age group.Fifteen patients (9.3%) were in coma and 12 patients (7.4%)had a decreased level of consciousness (stupor or drowsi-ness) on admission or during hospital stay.Radiological characteristics: The diagnosis of CVT was con-

firmed by computed tomography (CT) +CT angiography in26 patients (16%), by magnetic resonance imaging(MRI) +MR angiography in 83 patients (51%) and in 38patients (23%) by DSA. The remaining 9% of patientsrequired a combination of diagnostic tests to confirm thediagnosis.The most commonly affected location was the trans-

verse sinus (70%, with 54% left side involvement) fol-lowed by sigmoid sinus (46%, with 61% involvement

Table 1. Demographic, clinical and radiological characteristics (n = 162)

Gender Total

Male Female

n = 45 n = 117 p 95% CI

Age, n (%) 18 to 50 years 24 (53) 90 (77) 114 (70) 0.0045 (0.0789 - 0.3929)

> 50 years 21 (47) 27 (23) 48 (30) 0.0045

Clinical manifestation, n (%) Headache 33 (75) 100 (85) 133 (82) NS

Decreased visual acuity 7 (18) 16 (15) 23 (14) NS

Diplopia 8 (18) 15 (13) 23 (14) NS

Aphasia 8 (18) 16 (14) 24 (15) NS

Dysarthria 6 (13) 12 (10) 18 (11) NS

Motor symptoms 13 (29) 35 (30) 48 (30) NS

Sensory deficit 4 (9) 22 (19) 26 (16) NA

Seizure 11 (24) 29 (25) 40 (25) NS

Intracranial hypertension 18 (40) 25 (21) 43 (27) 0.04 (0.0345 - 0.3381)

Sensory impairment 5 (11) 22 (20) 27 (17) NA

Others* 6 (13) 18 (15) 24 (15) NS

ICU admission 19 (42) 53 (45) 72 (44) NS

Mechanical ventilation 6 (13) 13 (11) 19 (12) NS

Diagnostic imaging, n (%) Angio-CT 6 (13) 20 (17) 26 (16) NS

Angio-MRI 24 (53) 59 (50) 83 (51) NS

Digital angiography 9 (20) 29 (25) 38 (23) NS

Two or more methods 6 (13) 9 (8) 15 (9) NS

Number of affected sinus, n (%) 1 or 2 25 (56) 64 (55) 89 (55) NS

3 or 4 13 (29) 43 (37) 56 (35) NS

> 4 7 (16) 8 (7) 15 (9) NS

Brain involvement, n (%) SAH 9 (20) 28 (24) 37 (23) NS

Venous infarct 13 (29) 40 (34) 53 (33) NS

ICH 15 (33) 30 (26) 45 (28) NS

* Others: hemianopia, tinnitus, cranial nerve involvement, photophobia, phonophobia.

ICU: Intensive care unit, SAH: Subarachnoid hemorrhage, ICH: Intracerebral hemorrhage

NA: not applicable. NS: not significant

4 M. ALET ET AL.

of the left side) (Figure 1). In 95% of cases thrombosiswas located in superficial venous system (superior andinferior sagittal sinus, transverse or lateral sinus,straight sinus, sigmoid sinus and cortical veins).Twenty-four patients (15%) had bilateral compromiseof venous sinus.Venous infarction was identified in 53 patients (33%),

subarachnoid hemorrhage (SAH) in 37 (23%), intracere-bral hemorrhage (ICH) in 45 (28%) and subdural hema-toma (SDH) in 8 (5%). Forty-one percent of the patientsdid not show any lesions.Factors associated with CVT and related complications:

Overall, the most common identified factors associatedwith CVT were exposure to oral contraceptives (31%) andthrombophilia (28%) (Table 2).Table 2 shows gender differences of CVT. The most

common factor associated with CVT in women wasthe exposure to oral contraceptives (44%), followed bytransient hypercoagulable states related to pregnancy(3%) and puerperium (9%). Three of the four CVTcases during pregnancy occurred in the third trimesterand 90% of CTV postpartum cases occurred within the

first 4 weeks of the puerperium. In patients with con-traceptive use, 16 (31.4%) had positive thrombophiliatest. The most common predisposing factor for CVT inmen was thrombophilia (36%).The analysis of predisposing factors by age group

revealed a higher prevalence of cancer among thosepatients over 50 years compared to their younger counter-parts (30.0% vs. 7.5%, p < 0.001) and infections (11.0% vs.2.0%, p <0.001) (Table 2). Cancer types included solidtumors (n = 13), haematological (n = 10) and central ner-vous system (n = 2).Treatment: A total of 153 patients (94%) received

anticoagulation treatment at discharge. The most com-mon medication used was acenocoumarol (vitamin Kantagonist), followed by low molecular weightheparin. The average time between the onset of symp-toms and the start of treatment was 8 days (95% CI6-10 days).Endovascular treatment (mechanical thrombectomy/

thromboaspiration) was performed in 8 patients (5%).Hemicraniectomy was performed in 2 patients (1.2%) andventricular shunt in 3 (2%).

Figure 1. adapted from: Stam J. Thrombosis of the cerebral veins and sinuses. N Engl J Med 2005; 352(17): 1791-8.

CEREBRAL VENOUS THROMBOSIS IN ARGENTINA 5

Outcome measures: Functional outcomes at discharge wereavailable in 161 patients, of whom 131 (81%) achieved func-tional independence (mRS 0-2) at hospital discharge, 24(15%) were dependent (mRS 3-5) and 6 (4%) died. Follow-up data at 90 days were obtained from 137 patients(85%). During this period, 128 patients (93%) were func-tional independent (mRS 0-2), whereas 3 more patientsdied, with an overall mortality at 90 days of 6%(Figure 2). In 7 patients (4%), recurrence of CVT was identi-fied in the follow-up period, most commonly observedamong those age 50 years and older (10% vs. 2%, p = 0.03).

5. Discussion

CVT is challenging medical condition representingapproximately 1% of all strokes.6

We reported the results of the first ANR-CVT describ-ing baseline characteristics, clinical presentation, predis-posing factors, imaging findings, treatment and outcomemeasures.

We found that CVT primarily affects young individualsunder the age of 50 years and women. The median timesince symptoms onset to the initial medical assessmentwas 4 days. Headache was the most frequent presentingsymptom. The most affected sinus was the transversesinus (70%) followed by sigmoid sinus (46%). Overall, themost common identified predisposing factors were expo-sure to oral contraceptives (31%) and thrombophilia(28%). We found a higher prevalence of cancer amongpatients over 50 years. The great majority of patientsreceived anticoagulation treatment. Four out of fivepatients achieved functional independence (mRS 0-2) atdischarge with a low mortality rate (4%). We alsoobserved a low recurrence rate (4%).We conducted a literature review and compared our

results with CVT registries from around theworld (Tables 3 and 4) .3,6,8-30

We found in Pubmed 79 case reports from SouthAmerica, but no registry data. In Scielo and Lilacs wefound registries from Colombia8, Brazil9 and Uruguay.10

The VENOST study7 was the largest worldwide CVT

Table 2. Predisposing factors according to sex and age group (n=162)

Gender Total Age group

Male Female �50 >50

n = 45 n = 117 p 95% CI n = 114 n = 48 p 95% CI

Obesity, n (%) 14 (31) 22 (19) 36 (22) NS 22 (21) 14 (32) NS

Cancer, n (%) 9 (20) 16 (14) 25 (15) NS 8 (7.5) 17 (39) 0.0001 (0.1622 - 0.4058)

Rheumatic diseases, n (%) 1 (2) 3 (3) 4 (2) NA 4 (4) - NA

Trombophilia (n= 141), n (%) * 16 (36) 29 (25) 45 (28) NS 33 (31) 12 (27) NS

Antiphospholipid antibodies 5 (16) 7 (6) 13 (8) NS 7 (7) 4 (9) NA

Factor V Leiden 5 (16) 2 (2) 7 (4) 0.01 (0.0241 - 0.1639) 4 (4) 3 (7) NA

Hyperhomocysteinemia - 1 (1) 1 (0.6) NA 1 (1) - NA

MTHRF mutation - 1 (1) 1 (0.6) NA 1 (1) - NA

PAI 4G/5G 2 (6) 5 (4) 7 (4) NA 6 (6) 1 (2) NA

Prothrombin 20210 mutation - 3 (3) 3 (2) NA 2 (2) 1 (2) NA

Low C Protein 2 (6) - 2 (1) NA - 2 (5) NA

Low S Protein 1 (3) 5 (4) 6 (4) NA 6 (6) - NA

Activated protein C resistance - 2 (2) 2 (1) NA 2 (2) - NA

Contraceptives, n (%) - 51 (44) 51 (31) NA 50 (47) 1 (2) 0.0001 (0.2611 - 0.5744)

Pregnancy, n (%) - 4 (3) 4 (2) NA 4 (4) - NA

Puerperium, n (%) - 10 (9) 10 (6) NA 10 (9) - NA

Infection, n (%) 3 (7) 4 (3) 7 (4) NA 2 (2) 5 (11) 0.0001 (0.0181 - 0.1552)

Hormonal replacement, n (%) - 3 (3) 3 (2) NA 2 (2) 1 (2) NA

Cocaine use, n (%) 1 (2) - 1 (1) NA 1 (0.9) - NA

Chronic alcoholism, n (%) 1 (2) - 1 (1) NA - 1 (2) NA

CNS tumor (compression), n (%) - 1 (1) 1 (1) NA 1 (0.9) - NA

Autoimmune hepatitis, n (%) - 1 (1) 1 (1) NA - 1 (2) NA

Undetermined etiologies, n (%) ** 4 (8) 8 (7) 12 (11) NA 8 (9) 3 (6) NA

Unknown etiology, n (%) 4 (9) 5 (4) 9 (6) NA 8 (7.5) 1 (2) NA

MTHFR: Methylenetetrahydrofolate reductase, PAI: Plasminogen tissue activator inhibitor type 1 gene, CNS: Central nervous system.

NA: not applicable. NS: not significant

Note: *In 21 patients (13%), no information on thrombophilias was available. Positive thrombophilia was considered according to the cut-off point of each institution.

** Undetermined etiologies: Lumbar puncture, trauma, surgery, central catheter.

6M.A

LETETAL.

Figure 2. Disability assessed by modified Rankin Scale (mRS) at discharge and at 90 days grouped by sex The trends did not show significant differen-ces between groups and functional outcome. At discharge p = 0.6 and at 90 days p = 1. *The black box shows the percentage of patients with good functional out-come (defined as mRS �2)

CEREBRAL VENOUS THROMBOSIS IN ARGENTINA 7

registry, comprising 1114 patients receiving care at 25 hos-pitals in Turkey.We carried out a comparative analysis with registries

from across the globe. Our findings showed similarities indemographics when compared to CVT registries. CVTwas predominant in women (72%), occurring more fre-quently during childbearing age.6,11,31,32 The mean age inour study was 42 § 17 years, similar to North Americanand European studies,13 but higher than South Americanand Asiatic publications;8-10 this could be a possible expla-nation for the low rate of CVT in pregnancy (3%) andpuerperium (9%) in our study. Headache was the mostfrequent presenting symptom (82%) as in most studies (70to 90%).11,13,15,16,33,34 Overall, demographic data and clini-cal presentation was very similar to ISCVT and CEVETIS.Regarding male proportion (28%), it was similar toISCVT, South America, Europe, Turkey and two Africanregistries. There was up to 10-20% more males reported inregistries from Canada, USA and Asia.The most frequently affected sinus was the transverse

sinus (70%), followed by the sigmoid sinus (46%). We

observed no major regional differences in the affectedsinuses across studies. We found that 33% of patients hadvenous infarcts at the time of diagnosis and 56% had hem-orrhagic lesions (SAH 23%, SDH 5% and ICH 28%). Wefound a high association with CVT and SAH compared tomost registries. ICH could be observed in 27% of patientsfrom Asia (ASCVT and VENOST) and 28% in Europe(CEVETIS). In about 45% of patients we did not find alter-ations in parenchyma, similar to other registries. 23,35-37

The main differences that we found were regarding pre-disposing factors. A recent meta-analysis on CVTdescribed that hematological etiologies were the mostcommon ones in Africa, Asia, and South America, whilesystemic etiologies were the most common ones in Aus-tralia, Europe, and North America.6 We also observedcountry differences in the use of contraceptives amongpatients with CVT. For example, 44% of our patients hadexposure to contraceptives, compared to lower rates inAsian (11 to 14%) and Mexican (14 to 18%) studies. Wealso found a higher prevalence of cancer (15%) in compar-ison with most series across the world.6,38 Patients with

Table 3. Comparative table of the main variables in CVT registries around the globe. Data from our population is presented in the last row

Continent Global Asia Asia/Europe Europe Africa Oceania North America South America

Country Asia# China Saudi

Arabia

India Ir�an Jap�on India Pakistan Turkey Turkey Europe Tunisia Morocco Tunisia Sudan Australia Mexico Mexico Canada USA USA USA Colombia Brazil Argentina&

Study ISCVT ASCVT NIZAM VENOST CEVETIS NINN RENAMEVASC

Year of publication 2004 2019 2019 2019 2019 2016 2014 2012 2008 2017 2017 2012 2017 2014 2013 2008 2016 2018 2012 2017 2017 2009 2008 2012 2010

Number of patiens 624 812 243 26 71 151 22 428 109 1144 50 706 160 30 41 15 105 343 59 40.7 152 61 182 38 15 162

Mean age (years) 37 31 36 29.4 36.6 37 50.1 31.3 35 n/a 34.6 40 37.3 29 38 33.9 49 29 31 41 42 40 38 n/a 36 42

Female (%) 74.5 59 54.3 57.7 40.8 78.1 59.1 46.3 53 68 78 73.7 83.1 67 68 80 52 83.9 85 55 69 67 60 76 73 72

Headache (%) 88.8 90 90.1 65.4 66.2 85.4 59.1 88.3 81 87.2 96 n/a 71.3 80 83 100 n/a n/a 91.5 75 85.7 82 71 n/a 100 82

Seizures (%) 39.3 44 30.5 26.9 46.5 21.2 27.3 45.2 39 23.7 34 n/a 32.5 33 29 20 n/a n/a 20.3 25 13.6 31 32 18 33 25

Predisposing factor

Pregnancy / puerpe-

rium (%)

20.1 18 19.8 3.8 9.8 12.3 4.5 9.8 31 27 34 7.8 38.6 33 38 6.6 5 52.2 56.5 7.5 16.2 23 7 24 20 12

Use of oral contracep-

tives (%)

54.3 12 9.5 23 24.1 55.1 4.5 11.4 12 14 16 39.4 23.5 n/a 11 20 31 14.1 18 25 35.2 45 5 3 40 44

Infections (%) 12.3 11 17.7 15.3 22.5 9.9 - 2 18 8 4 8.3 8.7 26 34 13.33 n/a n/a n/a n/a 6.6 16 1 3 n/a 4

Cancer (%) 7.4 3 n/a - 5.6 5.3 - 1 4 5 6 7.4 3.7 3 7 - n/a n/a - 15 3.3 13 7 3 n/a 15

Trombophilias (%) 34.1 48 10.3 23 44.7 14.6 59.1 34 34 27 38 41.1 16.2 13 56 26.6 n/a 3 n/a 7.5 31.1 30 21 24 13 28

Cerebral venous

sinus

Multiple sinuses

involvement (%)

n/a n/a 85.6 80.3 n/a 41.7 45.4 n/a 50 18 8 n/a 71.25 n/a 46 20 57 n/a n/a n/a 83.7 69 n/a 40 50 44

Superior sagittal sinus

(%)

62 69.9 76.5 57.7 70.8 48.3 63.6 54.3 71 38.9 66 37.8 65 50 51 40 16 n/a 78 n/a 57.1 51 n/a 40 53 44

Transverse sinus (%) 85.91 26.5 81.1 73 68.2 45.7 54.5 47.7 47 73.4 62 71.7 60.6 1 50 1 56 n/a 11 n/a 15.3 n/a 86.4 69 n/a 56 73 70

Sigmoid sinus (%) 85.91 11.8 59.3 57.7 43.6 15.2 n/a 20.6 31 39.8 36 n/a 60.6 1 50 1 20 26.6 9 n/a n/a n/a 61.9 31 n/a 24 20 46

Deep sinus (%) 10.9 3.4 2.5 n/a 12.7 7.3 n/a 5.8 3 n/a n/a n/a 5 7 5 20 1 n/a 3.4 n/a 5.4 5 n/a 15 n/a 5

ICH in CT/MRI (%) 39 27 21.4 40 52 20.5 50 58 34 21.1 30 27.9 38.1 39.3 10 n/a n/a 38.4 n/a 32.5 43.2 44 28 68 n/a 51

Anticoagulation at

discharge (%)

83.3 68 n/a 88.5 n/a n/a 54.5 92.5 67 66.7 96 88.8 98.1 90 100 n/a n/a 71.1 81 90 100 84 68 93 80 94

Decompresive sur-

gery /Shunt/ ICH

evacuation (%)

3 2 n/a n/a 4.2 4 n/a 3.7 4 n/a n/a n/a 1.25 0 n/a n/a n/a n/a 3.4 - n/a 5 8 0 0 3

n/a: data not available. #Several Asian countries. &Data of the present work.

1. Informed combined as ’’lateral sinus’’

8M.A

LETETAL.

Table4.Comparative

tableofthemain

variablesin

CVTregistriesaroundtheglobe.Data

fromourpopulationispresentedin

thelastrow

Continent

Global

Asia

Asia/Europe

Europe

Africa

Oceania

NorthAmerica

South

America

Country

Asia#

ChinaSaudiArabia

India

Ir� an

Jap� on

India

PakistanTurkey

Turkey

Europe

Tunisia

MoroccoTunisia

Sudan

AustraliaMexicoMexico

CanadaEEUU

EEUU

EEUU

Colombia

BrazilArgentina&

Study

ISCVTASCTV

NIZAM

VENOST

CEVETIS

NIN

NRENAMEVASC

Year

2004

2019

2019

2019

201920162014

2012

2008

2017

2017

2012

2017

2014

2013

2008

2016

2018

2012

2017

2017

2009

2008

2012

2010

Death

inhospitalization

(%)

4.3

3.3

2.8

n/a

5.6

11.3

-7.7

6.4

-4

n/a

3.7

10

7.3

13.3

97.3

3.4

59.9

113

--

4

Disability(m

RS3-5)

atdischarge(%

)

14.6

13

23

n/a

25.4

14.5

13.6

25.7

39.4

10

n/a

7.1

n/a

27

10

40

n/a

30

33.9

20

30

19

25

n/a

13

15

CVTrecurrence

(%)

2.2

1n/a

n/a

n/a

4n/a

5.1

n/a

n/a

n/a

4.4

1.2

n/a

2.5

n/a

n/a

3.5

n/a

n/a

n/a

n/a

4n/a

-4

n/a:datanotavailable.#SeveralAsian

countries.

&Dataofthepresentwork.

1.Inform

edcombined

as’’lateralsinus’’

CEREBRAL VENOUS THROMBOSIS IN ARGENTINA 9

cancer are particularly vulnerable to hypercoagulabilityeither related to the underlying malignancy or treatmentcomplications.39

A few studies reported age cut off points when analyz-ing CTV predisposing factors. A study from M�exico3 used40 years, a study from China28 used 44 years and a studyfrom Turkey7 used 18-36, 37-50 and 51+ years. For agesubgroups, the obstetric causes were more frequent inyounger patients, whereas infection and malignancy weremore often seen in older patients.The use of anticoagulation treatment in different parts

of the world was recently published.6 They found that itvaried between the continents and was surprisingly lowat 57% in South American countries. In our registry, anti-coagulation treatment at discharge was 94%, with ahigher rate compared to some series from Asia or NorthAmerica. According ISCVT,11 more than 80% of thepatients were treated with anticoagulants, indicating aconsensus on the efficacy and safety of anticoagulation inCVT. Personal beliefs regarding the benefits of this ther-apy for CVT or knowledge to action gaps could explainthe difference in some regions. Further studies would beneeded to explain this phenomenon (Figure 3).Only the treatment at discharge was collected in our

study. In Argentina, as recommended in the latest guide-line,40 the standard treatment scheme starts in the acutestage with heparin (mostly LMWH), followed by VKAagents at discharge to prevent recurrent CVT and othervenous thromboembolic events. Some patients were dis-charged early or derived to rehabilitation centers, and ace-nocoumarol treatment was started in the follow up. Insome patients with malignancy related CVT, the treatingphysician might had opted for heparin at discharge.The comparison of outcome measures among CVT reg-

istries is highly variable. For example, we observed a 4%mortality rate at discharge, whereas other registriesreported no deaths (VENOST, Turkey) up to 13.3% inSudan. Similar variability was observed in functional sta-tus at discharge. In addition, we observed a 15% disabilityat discharge, whereas the ISCVT reported 7% reaching ithighest prevalence in Pakistan (39.4%) or Sudan (40%).Given methodological differences and lack of patient-leveldata a reliable statistical comparison was not possible.After CVT, the risk of venous thrombotic events is esti-

mated at 2% to 3% for a new CVT and 3% to 8% for extra-cranial events. Venous thrombosis after CVT is morefrequent among men and in patients with polycythemia/thrombocythemia. Cancer/malignant hemopathies, andunknown CVT causes were found to be at higher risk ofrecurrence.41,42 We had a 4% of patients with CVT recur-rence, quite similar to the reviewed registries with followup information (from 1% to 5.1%). Is important to remarkthat follow-up time differs in every study, therefore wecan only make an estimation.Our study has limitations that deserve comment. First,

as in many multicenter studies, we cannot rule out the

Figure 3. Comparison of anticoagulation rates at discharge among different CVT registries

10 M. ALET ET AL.

possibility that differences in data collection, comple-tion of investigations and treatment decisions mayhave influenced our results. Second, we were unableto determine the time of the CVT diagnosis with brainimaging. Third, loss of follow up represented 7% at90-days. Fourth, given that the decision to proceedwith more comprehensive investigations were at thediscretion of the treating physician, 13% (n = 21) of thepatients have limited information on thrombophilias.We do not have specific information regarding thetotal number of patients tested for elevated homocyste-ine and MTFRH mutations, commonly completed inacademic centers. The low prevalence of these condi-tions in CVT and our low sample size might reflect anunderestimation of the true prevalence of hyperhomo-cysteinemia and MTFRH mutation in our study.Finally, our study may not represent the totality ofpatients with CVT in Argentina as oligosymptomaticpatients may have been missed when presenting toother institutions.Despite these limitations, our study is the first comprehen-

sive report of the Argentinian National multicenter registryon CVT. Our findings are useful for increase public andphysician’s awareness and planning resources for the opti-mal management of CVT in Argentina. A recent article aboutcontinental disparities in CVT,6 with data from 7048 patientsfrom all over the world, showed that some continents likeSouth America had limited number of published data com-pared to other continents like Asia and Europe. Our litera-ture review highlighted similarities and differences inbaseline characteristics, clinical presentation, most commonpredisposing factors, treatment and outcomes between ourstudy and CVT registries from across the globe.

Our results are the starting point for the publication ofthe first best practice guidelines for the diagnosis andmanagement of CVT in Argentina.Furthermore, the comparison with other registries is a

call for international collaborations as joint efforts toimprove our understanding on regional differences in thediagnosis and management of CVT.

Declaration of Competing Interest

All authors certify that they have no affiliations with orinvolvement in any organization or entity with any finan-cial or nonfinancial interest in the subject matter or materi-als discussed in this manuscript.

Acknowledgements: Dr. Saposnik is supported by theCareer Scientist Award from Heart and Stroke Foundation ofCanada following an open, peer-reviewed competition.

Appendix: Complete list of other authors andparticipating centers

The following centers and investigators participated inthe ANR-CVT. The number of patients included at eachcenter is given in parentheses:FLENI, Ciudad Aut�onoma de Buenos Aires (29, Amer-

iso S., Alet M. and Pujol-Lereis V.); Hospital Brit�anico,Ciudad Aut�onoma de Buenos Aires (24, Bonardo P., Ban-deo L., Gonz�alez F., Pacio G. and Saucedo M.); HospitalItaliano de Buenos Aires, Ciudad Aut�onoma de BuenosAires (14, Cea C. and Zurr�u M.); Clínica La Sagrada Fami-lia. Ciudad Aut�onoma de Buenos Aires (13, Ciardi C.,Chasco M. and Cirio J.); HIGA Gral. San Martín de LaPlata, Buenos Aires (9, Montes M. and Tumino L.);

CEREBRAL VENOUS THROMBOSIS IN ARGENTINA 11

Sanatorio de la Trinidad Mitre, Ciudad Aut�onoma deBuenos Aires (9, Persi G.); Hospital Cullen, Santa Fe (8,Galindo A., Martínez C. and Noguera M.); Hospital SanBernardo, Salta (7, Orzuza G.); Hospital Julio Cecilio Per-rando, Chaco (6, Cuculic M.); CEMIC, Ciudad Aut�onomade Buenos Aires (6, Romano M.); Hospital Lagomaggiore,Mendoza (5, Giner F.); Sanatorio de los Arcos, CiudadAut�onoma de Buenos Aires (5, G�omez-Schneider M. andPiedrabuena M.); Hospital Provincial del Centenario,Santa Fe (4, Martínez-Lorezín R.); Complejo M�edico Poli-cial Churruca-Visca, Ciudad Aut�onoma de Buenos Aires(4, Povedano G.); Hospital General de Agudos J. M.Ramos Mejía, Ciudad Aut�onoma Buenos Aires (3, LeperaS. and Rey R.); Hospital Dr. Guillermo Rawson, San Juan(3; Lucato D. and Quiroga-Narv�aez J.); Hospital C�esarMilstein, Ciudad Aut�onoma de Buenos Aires (3, EsnaolaM.); Clínica Regional del Sud, C�ordoba (2, Viglione J.);IMAC - Instituto M�edico de Alta Complejidad, Salta (2;Alem�an A.); Hospital �Angel Cruz Padilla, Tucum�an (2,Cossio J.); Hospital Dr Arturo O~nativia, Buenos Aires (1,Isaac C.); Hospital SAMIC de Alta Complejidad Goberna-dor Cepernic - Presidente Kirchner, Santa Cruz (1, SabioR.); Neuromadryn, Chubut (1, García-P�erez F.).

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